Side effects of Pfizer/BioNTech (BNT162b2) COVID-19 vaccine reported by the Birzeit University community

Background The Pfizer BioNTech COVID-19 vaccine was the first to receive emergency authorization and approval from the FDA. Therefore, it is preferred by most recipients; however, many people are concerned about the vaccine’s side effects. At the time of the study, December 2021, Palestine lacked a national reporting system for monitoring adverse vaccine effects. Therefore, this study investigates the post-vaccine adverse events following the Pfizer/BioNTech COVID-19 Vaccine administration in Palestine and identifies the occurrence, extent, and severity among university staff, employees, and students at Birzeit University. Method A questionnaire-based retrospective cross-sectional study was conducted using a university website (Ritaj), social media platforms (e.g., Facebook and Telegram), and in-person interviews. The Chi-square, Fisher’s exact, and McNemar’s tests were used to investigate significant relationships. Data were analyzed using SPSS version 22. Results In total, 1137 participants completed the questionnaire, 33.2% were males, and the mean age was 21.163 years. All participants received at least one dose of the Pfizer-BioNTech COVID-19 vaccine. Approximately one-third of participants reported no adverse effects after receiving the first, second, or third doses (34%, 33.6%, and 32.5%, respectively). The most commonly reported adverse events were fever, chills, headache, fatigue, pain and swelling at the injection site, muscle pain, and joint pain. Allergic reactions were reported by 12.7% of the participants; furthermore, participants with a history of allergy or anaphylaxis before vaccination had a significantly higher tendency for post-vaccination allergic reactions. Eight participants reported rare side effects, including 7 (0.6%) cases of thrombocytopenia and one (0.1%) case of myocarditis. Males aged less than 20 years and smokers were significantly less likely to complain of adverse events. The number of reported side effects was significantly higher after the second vaccine dose than after the first dose. Finally, participants infected with COVID-19 before vaccination was significantly associated with side effects such as fever, chills, shortness of breath, and persistent cough. Conclusion In this study, the most common post- BNT162b2 Vaccination reported self-limiting side effects similar to those reported by Pfizer/BioNTech Company. However, higher rates of allergic reactions were reported in this sample. Rare side effects, such as thrombocytopenia and myocarditis, were reported by 8 participants. COVID vaccines have been developed at an accelerated pace, and vaccine safety is a top priority; therefore, standard monitoring through a national adverse event reporting system is necessary for safety assurance. Continuous monitoring and long-term studies are required to ensure vaccine safety. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-022-07974-3.

the United States of America, the Vaccine Adverse Event Reporting System has been implemented. In the United Kingdom, the Yellow Card Scheme facilitates the early detection, investigation, and analysis of adverse events following vaccination (AEFIs) and adverse events of special interest (AESIs). Currently, Palestine lacks a national reporting system for monitoring vaccine adverse effects. Adverse events reporting and tracking systems in Palestine are essential as various vaccinations became available and approved with an Emergency use status [13].
This study investigates the post-vaccine adverse events following the Pfizer/BioNTech COVID-19 Vaccine administration in Palestine to alleviate the incomplete clinical trial gap and support the national strategic readiness and response plan. Furthermore, to identify the occurrence, extent, and severity of adverse events among university staff, employees, and students at Birzeit University and compare the incidence of these side effects between the first, second, and third doses and the data published by Pfizer company. Finally, this study aimed to predict the post-vaccination side effects based on individual predisposing factors such as age, gender, smoking status, food/drug allergy, comorbidities, and COVID-19 infection before vaccination.

Study design and sample
A questionnaire-based retrospective cross-sectional study was conducted at Birzeit University in Palestine, which started the vaccination of the university community in September 2021, from December 13, 2021, to March 29, 2022. The study included participants aged 18 years and older who received at least one dose of the Pfizer/BioNTech COVID-19 Vaccine. The questionnaire was distributed through the university website (Ritaj), social media platforms (e.g., Facebook, Telegram, etc.), and in-person interviews. 1496 participants were included in this study, while 375 were excluded because they refused to participate, had an incomplete response to the questionnaire, or received other types of COVID-19 Vaccines.

Questionnaire (survey)
The questionnaire was prepared in English, following a thorough literature review [14,15]. The researchers examined and evaluated the questionnaire elements at different sessions. Furthermore, it was expertly translated into Arabic since it is the official language of the target population (Additional file 1).
A pilot study was conducted to confirm questionnaire consistency among 32 vaccinated COVID-19 individuals, who were asked to complete the questionnaire and provide feedback on its clarity, relevance, and construction. These pilot study responses were not included in the formal evaluation, and modifications were made to the final Arabic draft based on the participants' reviews.
The questionnaire included five sections with 27 questions formulated as open-and closed-ended multiplechoice questions besides two short essay questions. The first section included nine questions concerning demographic information, such as gender, age, weight, height, employment, chronic diseases, allergic reactions, and smoking status. The second section included four questions about infection status with SARS-Cov-2 before vaccination. The third section consisted of 4 questions on the COVID-19 vaccines, such as the type, the number of doses received post-vaccination counseling and allergic reactions after vaccination. The fourth section, "Pfizer-BioNTech side effects, " consists of a list of 23 possible side effects divided into two categories as local or systemic adverse events according to the world health organization's global manual on surveillance of adverse events following immunization [16]. Adverse events were chosen using the WHO, CDC leaflet, and reports published by randomized control trials on the Pfizer-BioNTech vaccine [5,17]. The local adverse events compromised of pain at the injection site, and swollen armpit glands, while systemic adverse events include fever, chills, headache, increase in blood pressure, increase in heart rate, shortness of breath, persistent cough, chest pain, voice hoarseness, dizziness, nausea, vomiting, diarrhea, abdominal pain, tiredness and fatigue, muscle pain (myalgia), joint pain, swollen ankles and feet, and sleep disturbances. In addition to side effects that were selfnoticed as menstrual cycle changes and tinnitus. Also, space was provided for reporting other uncatalogued side effects which may be experienced. Other questions in this section included the onset and duration of experienced side effects, participant's attitude after vaccination, and any doctor's visit or hospital admission due to severe side effects. Finally, the last section included four questions about the infection status with SARS-Cov-2 after vaccination.

Statistical analysis
The data were analyzed using IBM Statistical Package for the Social Sciences (SPSS) version 22. Descriptive statistics were used to analyze the data. Frequencies and percentages were measured for categorical data, whereas means and standard deviations were measured for continuous data to be used as descriptive statistics. First, questions were recoded and categorized; height and weight were computed to BMI and then categorized based on BMI classification: underweight (below 18.5), normal weight (18.5-24.9), overweight (25.0-29.9), and obese (≥ 30.0) [18]. Next, ages were divided into two groups (lower than 20, 20, and more years old).
Chi-square (χ 2 ) or Fisher's exact tests were performed to investigate the association between participants' demographics and post-vaccination side effects for the first and second doses. Chi-square (χ 2 ) or Fisher's exact tests were also applied to investigate the association between participants' demographics and onset plus side effects duration. In addition, McNemar's tests were conducted to compare the incidence of each side effect between the first and second shots. All inferential tests were performed considering a confidence interval (CI) of 95% and a significance value of p < 0.05.

Ethical considerations
All participants were given a brief introduction to the study's objectives and were asked to provide their informed consent before completing the questionnaire. This consent procedure was approved by the Ethics Committee of the Research Ethics Committee at the Faculty of Pharmacy, Nursing, and Health Professions, Birzeit University (reference number BZU-PNH-2103).

Post-vaccination side effects
Approximately one-third of participants reported no adverse effects after receiving the first, second, or third dose of the Pfizer vaccine, with 34%, 33.6%, and 32.5%, respectively. Participants who received more than one dose experienced more side effects. The most commonly reported adverse effects were fever, chills, headache, fatigue, pain and swelling at the injection site, muscle pain, and joint pain. Allergic reactions following vaccination, such as allergic skin reactions (itching, burning, and rash), angioedema, shortness of breath, coughing, and significant swelling of the tongue or lips, were reported by 144 (12.7%) participants (Fig. 2). Rare and severe side effects that require medical attention were reported by eight participants, including one (0.1%) case of myocarditis and 7 (0.6%) cases of thrombocytopenia.
A relatively high percentage (13%) of participants reported shoulder injury related to vaccine administration (SIRVA) (Fig. 3A). Furthermore, a considerable percentage (13%) of the participants experienced at least one type of allergic reaction after receiving the Pfizer BioNTech vaccine (skin rash, persistent cough, shortness of breath, angioedema, swelling of the tongue or lips) (Fig. 3b). In addition, 51.7% of participants took pain relievers post-vaccine for side effects management (Fig. 3c). Furthermore, 45 (4%) missed more than two days of work or school due to post-vaccination side effects or allergic reactions to the vaccine (Fig. 3d), and 49% of vaccine recipients were not counseled about the vaccine's side effects (Fig. 3e).
As shown in Table 2, McNemar's test results revealed that the proportion of respondents who reported systemic adverse events after the second vaccine dose and did not report after the first dose was statistically significantly increased (p-value < 0.05). These adverse events include; chills (14.2%), Chest pain (6%), Dizziness (9.9%), Ringing in the ears (Tinnitus) (4.9%), tiredness and fatigue (12.5%), Joint pain (10%), over sleepiness, and decreased sleep quality (4%), and (9.5%) of females reported menstrual cycle changes after the second dose only.

Association of demographic characteristics of the participants and side effects after the second dose
There were significant associations between participants who suffered from drug/food allergy with the frequencies of all adverse events following the second vaccine shot except tiredness and fatigue, joint pain, and swollen armpit glands. The reported differences are shown in Fig. 6. Moreover, the presence of comorbidities was statistically significant with the incidence of side effects such as an increase in heart rate (16.7%, p-value = 0.003), shortness of breath

Discussion
As information about the COVID-19 vaccine continues to evolve, and with the FDA approval for human use, post-marketing studies are necessary to ensure safety, efficacy, and use. Therefore, this study was conducted as a post-marketing survey of the Pfizer-BioNTech vaccine in Palestinian society. First, we investigated the incidence of side effects and reinfection rates following the administration of the Pfizer-BioNTech vaccine, then compared the incidence of these side effects between the first, second, and third doses. In addition, we predict the postvaccination side effects based on predisposing factors. Adverse effects were reported in more than two-thirds of the study participants. Most of the side effects were experienced within 12 h of vaccination and persisted for 1-3 days. This finding is similar to a systemic review of Pfizer-BioNTech COVID-19 Vaccine side effects and other COVID-19 vaccines, where participants suffered from post-vaccination adverse effects after the three doses, and to an Egyptian study where adverse events resolved a couple of days after onset [14,[19][20][21]. These side effects are related to the normal immune system's response to the vaccine constituents resulting in the transient production of cytokines that cause inflammation in the muscles, blood vessels, and other tissues.
A wide range of common side effects, including fever, chills, headache, fatigue, pain and swelling at the injection site, muscle pain, and joint pain, were reported by participants. In addition, some side effects were reported less commonly, such as increased blood pressure, increased heart rate, vomiting, diarrhea, swollen armpit glands, swollen ankles and feet, and others. These findings are consistent with those reported in the Pfizer-BioNTech factsheet by the Food and Drug Administration (FDA) and many other studies [22,23]. Myocarditis was reported in many published case reports, case series, and retrospective studies following COVID-19 mRNA immunization in young people (18-25 years) after receiving the second vaccination dose; however, the incidence was rare [24,25]. Many factors must be considered when assessing the risk of myocarditis, including patient factors, medical history, and SarsCov2 infection history [26]. The Centers for Disease Control and Prevention (CDC) reported that infection with the Sars-cov2 virus increases the risk for myocarditis; therefore vaccine's benefits in preventing COVID-19 infection, hospitalization, and intensive admissions and death exceed the potential risk of myocarditis [27]. The localized lymphadenopathy (enlarged axillary nodes) reported in this study aligns with the first Therapeutic Goods Administration's COVID vaccine safety report of 2022, which is more  common in the mRNA booster dose [28,29]. Enlarged axillary nodes are a normal response caused by a robust vaccine-elicited immune response due to the proliferation of rapidly activated immune cells (residual effector cells) from previous doses [30,31]. The severity of most experienced side effects reported after each of the three vaccine doses was mild to moderate and self-limiting, similar to the published results of the phase III Pfizer clinical trial, with the majority occurring after the second dose [22,23,32]. Interestingly, some side effects after the third dose were reported more frequently, including fatigue, pain at the injection site, myalgia, and arthralgia, which is inconsistent with the Food and Drug Administration (FDA) report on the booster dose [3].
Specific Side effects types and severity reported by participants differed slightly from the CDC, the FDA, or other studies. For example, as shown in Fig. 7, there is an increase in the occurrence of fever (35.7%, and 33.1% for first and second doses, respectively) compared to the CDC (3.7% and 15.8%). Furthermore, study participants reported less injection site pain and redness (30.1%, 25.8%) than what is reported on the Pfizer-BioNTech factsheet (83.1%, 77.8%) and other regional studies [6,14,33]; a similar finding was reported in a Bahraini study where the incidence of fever and pain at the injection site after the first dose (25%, 43%).
A considerable percentage (13%) of the participants experienced at least one type of allergic reaction after receiving the Pfizer BioNTech vaccine (skin rash, persistent cough, shortness of breath, angioedema, swelling of the tongue or lips) (Fig. 3d). However, anaphylactic reactions associated with vaccines are rare, and it has been reported at a rate of 1:125,000 doses for the Pfizer/BioN-Tech COVID-19 vaccine, perhaps due to PEGylated nanoparticles (PEG2000) as excipients [32]. Participants with a history of allergy or anaphylaxis prior to vaccination had a significantly higher tendency for post-vaccination allergic reactions and side effects caused by a stronger immune response. The injection of foreign materials triggers a non-specific inflammation caused by the activation of macrophages, dendritic cells, eosinophils, basophils, and especially innate type 2 lymphoid cells and the decreased activation threshold of effector cells (mast cells among them) to non-IgE activating factors [34]. In a cohort study to investigate the association of high-risk allergy history with allergy symptoms post COVID-19 vaccination, subjects with food and drug allergies were more susceptible to experiencing a post-vaccination allergic reaction [35].
Therefore, healthcare providers and institutions are encouraged to follow the CDC's COVID-19 vaccination guidance, including pre-vaccination screening forms, enforcing the recommended 15-min post-vaccination observation periods, and having the necessary reserves available to handle severe allergic reactions.
The participants' demographic data revealed a significant percentage of females, young, non-smokers, and individuals of normal weight. These findings refer to the large percentage of student participation and a higher percentage of female vs. male students at Birzeit University (62% vs. 38%, respectively) [36].
Females experienced a higher incidence of side effects after receiving the Pfizer-BioNTech vaccine. These gender variations were also found in previous vaccines, as reported by a 2019 study on allergic reactions following the 2009 flu vaccine [37]. Gender biological variations, including hormones, genes, immunologic distinctions, pharmacokinetics, and pharmacodynamics, affect vaccine response [19,38]. The difference in immune response between males and females was demonstrated in a study by Yale University in 2020, in which the blood samples of females taken following COVID-19 infection showed a higher t-cell response than male blood samples [39]. Therefore, vaccine manufacturers should consider the higher female immune response and offer a reduced vaccine dose for females, reducing the side effects and maintaining the same efficacy or considering a later booster dose [40]. Many studies have addressed smoking, vaccinations, and the risk of COVID-19 infections. The CDC developed its recommendation for the necessity of smoker vaccination based on smokers' high risk of COVID infections. Smokers who participated in the study experienced a lower prevalence of post-COVID-19 vaccination side effects than non-smokers. This finding is supported by other studies where nonsmokers who received the COVID-19 vaccine experienced a higher incidence of pain and swelling at the injection site after the first dose than smokers [15]. Smoking could affect Ferrara demonstrated that antibody titers dropped rapidly in COVID-19 vaccinated smokers [41]. Elderly patients and patients with comorbid diseases prioritized vaccinations according to many vaccine protocols owing to a higher risk of COVID-19 infections and complications. Participants with comorbidities are assumed to have depleted responses to immunogens; thus, they are more susceptible to experiencing reduced side effects following any Vaccination [42]. In this study, participants with comorbid diseases were at higher risk of developing post-vaccination side effects, including increased blood pressure, heart rate, shortness of breath, voice hoarseness, dizziness, nausea, diarrhea, abdominal pain, and myalgia (muscle pain). These findings support the results of studies from the Arab region by Ma'mon M. Hatmal [31] and Saudi Arabia by Alghamdi et al. [43], which showed that chronic diseases are associated with developing post-vaccination side effects. However, further studies are needed to explain the causes of increased side effects following different COVID-19 vaccinations in comorbid people.
Regarding pre-vaccination COVID-19 infection, there was a significant association between previous COVID-19 infection and post-vaccination adverse effects. Participants who had COVID-19 infection before vaccination experienced higher post-vaccination side effects. This result was consistent with a multinational study among Arab populations and an Italian study [15,32]. In this scenario, the natural vaccine infection of COVID-19 simulates the first vaccination dose, and side effects are more common after the second dose of the vaccine in patients who have never been infected. Thus, the first dose of the vaccine may serve as a booster dose in previously infected COVID-19 patients, causing an ADR to occur more frequently.

For the First dose
In Pfizer report In our study The CDC has developed training modules for healthcare workers (HCW) delivering the Pfizer-BioNTech (COMIRNATY ® ) COVID-19 vaccine to ensure good HCW practice, professional vaccine administration, and storage, as well as to provide HCWs with scientific data regarding vaccine safety and efficacy [44]. Adherence to vaccine protocols in administration, counseling, and patient assessments and providing patients with vaccine information sheets are essential to prevent complications and allergic reactions and ensure patient safety. Unfortunately, many HCWs did not implement the COVID-19 vaccination guidance designed by vaccine manufacturers, increasing the risk of improper vaccination techniques of intramuscular percutaneous injection into the patient's arm [45]. However, Reports of SIRVA with the mRNA COVID-19 vaccines are rare, and it is hard to specify how common SIRVA is with the COVID-19 vaccine [46].
Nonetheless, this finding suggests that the healthcare field should be more attentive to vaccine-related training and education for HCWs to guarantee vaccine administration safety and good clinical practice. Furthermore, prevent complication that leads to missed days of work or school. In this study, 23% of participants reported work or school absence for a couple of days due to Pfizer-BioNTech vaccine side effects, which could influence the economy in the long term. A similar finding was reported in a US survey "AstraZeneca and Pfizer COVID vaccine shots lead to missed work days. " [47].

Strengths
With increasing studies on the side effects of COVID-19 vaccines worldwide, our study is the first to evaluate the side effects of the Pfizer-BioNTech vaccine among Palestinians with a large sample size (N = 1137) and high educational level. Furthermore, our study's main strength was the lack of opportunity for non-response bias because most questionnaires were filled based on faceface interviews.
In addition, open-ended responses were primarily used in the survey, while close-ended answers (Yes/No) were rarely used, expanding the participants' information.

Limitations
As the study was conducted at a university, a higher percentage of responses were received from young people aged 18-23 year old (students) compared to older people aged > 30 year old (university staff ), the age groups were unevenly distributed, causing the participant proportions in different groups to be biased. Second, although only a tiny percentage of questionnaire responses were collected online via Google Forms, differences resulted from exposure, interpretation, or misclassification of side effects. Third, this study was a self-reported study based on participant perception of adverse events, which was not clinically evaluated or confirmed, and could be related to other factors besides the vaccine; therefore, this study was unable to make a causality assessment of serious events as recommended by the WHO. Furthermore, uncovering severe side effects and establishing a direct causal relationship will require further research and studies. Therefore, further studies are recommended to cover the entire country, including the occupied Palestinian territories, to confirm the initial results of this study.

Conclusion
COVID vaccines have been developed at an accelerated pace, and vaccine safety is a top priority; in this study, the most common post-BNT162b2 Vaccination reported self-limiting side effects similar to those reported by Pfizer/BioNTech Company. However, higher rates of allergic reactions were reported in this sample. In addition, rare side effects, such as thrombocytopenia and myocarditis, were reported by 8 participants. Therefore, standard monitoring through a national adverse event reporting system is necessary for safety assurance; continuous monitoring and long-term studies are required to ensure long-term vaccine safety.

Additional file 1. Study Questionnaire.
Author contributions ADA: Conceptualization, data curation, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing, review, and editing. SS and RRA: conceptualization, data curation, investigation, methodology, resources, software, validation, visualization, writing-original draft, and writing-review and editing. NA-S, HAN, AR: conceptualization, formal analysis, methodology, validation, visualization, and writing-review & editing. All authors read and approved the final manuscript.

Funding
No funding was received from any party for the data collection and publishment of this research.

Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate All participants were given a brief introduction to the study's objectives and were asked to provide their informed consent before completing the questionnaire. This consent procedure was approved by the Ethics Committee of the Research Ethics Committee at the Faculty of Pharmacy, Nursing, and Health Professions, Birzeit University (reference number BZU-PNH-2103). The Ethics Committee of the Research Ethics Committee at the Faculty of